Mechanisms leading to in vivo ceftolozane/tazobactam resistance development in Pseudomonas aeruginosa

REIPI researchers, led by H. Son Espases Group, Have characterized the mechanisms driving resistance development to the new antipseudomonal combination ceftolozane/tazobactam in 5 patients treated for MDR Pseudomonas aeruginosa infections. In all five cases, the same clone was detected for the susceptible/resistant pairs; the widespread ST175 high-risk clone in four of the cases and ST179 in the remaining case. Genomic analysis of the four initial ST175 isolates revealed an OprD mutation responsible for carbapenem resistance and an AmpR mutation responsible for AmpC overexpression and β-lactam resistance. The final isolates had developed ceftolozane/tazobactam and ceftazidime/avibactam resistance, and each additionally showed a mutation in the β-lactamase AmpC. The cloned AmpC variants showed greatly increased ceftolozane/tazobactam and ceftazidime/avibactam MICs compared with wild-type AmpC, but, in contrast, yielded lower MICs of imipenem, cefepime and particularly piperacillin/tazobactam. On the other hand, ceftolozane/tazobactam resistance development in ST179 was shown to be driven by the emergence of the extended-spectrum OXA β-lactamase OXA-14, through the selection of a mutation from OXA-10. Therefore, modification of intrinsic (AmpC) and horizontally acquired β-lactamases appears to be the main mechanism leading to ceftolozane/tazobactam resistance in MDR P. aeruginosa.